The iPSYCH2012 case-cohort sample: new directions for unravelling genetic and environmental architectures of severe mental disorders

Abstract

The Integrative Psychiatric Research (iPSYCH) consortium has established a large Danish population-based Case-Cohort sample (iPSYCH2012) aimed at unravelling the genetic and environmental architecture of severe mental disorders. The iPSYCH2012 sample is nested within the entire Danish population born between 1981 and 2005, including 1 472 762 persons. This paper introduces the iPSYCH2012 sample and outlines key future research directions. Cases were identified as persons with schizophrenia (N=3540), autism (N=16 146), attention-deficit/hyperactivity disorder (N=18 726) and affective disorder (N=26 380), of which 1928 had bipolar affective disorder. Controls were randomly sampled individuals (N=30 000). Within the sample of 86 189 individuals, a total of 57 377 individuals had at least one major mental disorder. DNA was extracted from the neonatal dried blood spot samples obtained from the Danish Neonatal Screening Biobank and genotyped using the Illumina PsychChip. Genotyping was successful for 90% of the sample. The assessments of exome sequencing, methylation profiling, metabolome profiling, vitamin-D, inflammatory and neurotrophic factors are in progress. For each individual, the iPSYCH2012 sample also includes longitudinal information on health, prescribed medicine, social and socioeconomic information, and analogous information among relatives. To the best of our knowledge, the iPSYCH2012 sample is the largest and most comprehensive data source for the combined study of genetic and environmental aetiologies of severe mental disorders.

Figure 1

The selected samples were correlated with their DNSB identifiers and entered into an in-house developed selection database (Step 1 and 2). Sample identities were then validated and assigned a pseudonymized unique ID (Step 3) before cutting two discs of 3.2 mm of dried blood into a 96-well PCR plate (Step 4). Proteins were washed of the blood spots and stored at −80 °C before DNA was extracted using Extract-N-Amp Blood PCR Kit (Sigma-Aldrich, St Louis, MO, USA) (Step 5). DNA was amplified in triplicates using REPLI-g (Qiagen, Hilden, Germany) and combined to a single sample (Step 6). Finally, concentrations were quantified using Quant-iT picogreen (Invitrogen, Carlsbad, CA, USA) (Step 7) and a genetic fingerprint established using the iPLEX pro Sample ID panel (Agena Bioscience, Hamburg, Germany) (Step 8) before aliquoting a fraction of the sample for genotyping (Step 9).

Figure 2

Scatterplot of the first two principal components colored according to parental region of birth. Big circles indicate mean values for the given parental group. Crosses indicates both parent born abroad within the region indicated by the color. Absence of cross indicate one Danish born parent and one parent born in the region indicated by the color. Persons with unknown information on parental region of birth (N=1088) and mixed parentage are not shown (N=366).